Process for producing a depressant-like effect on the central nervous system



3,097,136 PROESS FOR PRQDUCKNG A DEPRESSANT-LIKE EFFECT ON THE CENTRAL NERVQUS SYSTEM Erik F. Godefroi, Detroit, V Harold Maddox, Huntington Woods, and Robert F. Parcell, Ann Arbor, Mich, assignors to Parke, Davis 8: Company, Detroit, Mich, a corporation of Michigan No Drawing. Filed Apr. 4, 1960, Ser. No. 19,474 Claims. (Cl. 167-65) This invention relates to a process for producing a depressant-like effect upon the central nervous system of mammals and to compositions useful in producing the aforementioned effect. More particularly, the invention relates to a process for producing a depressant-like effect upon the central nervous system of mammals by introducing a l-phenylcyclohexylamine compound of formula,

or a non-toxic acid addition salt thereof into a mammal and to compositions containing such l phenylcyclohexylamine compounds and/or nontoxic acid addition salts thereof; Where R and R are hydrogen or *alkyl radicals, the sum of the carbon atoms in the alkyl radicals being less than 5, or R and R are combined and together represent a polymethylene radical containing 4 to 6 carbon atoms inclusive.

The term non-toxic acid addition salt as used herein includes any acid addition salt which is not substantially more toxic than an equal weight of the free base of the l-phenylcyclohexylamine compound from which it is derived. Some examples of such salts are the mineral acid salts such as the hydrochloride, hy'drobromide, sulfate and phosphate; organic acid salts such as the succinate, benzoate, acetate, p-toluenesu-lfonate and benezenesulfonate; and salts with other strong acids such as the sulfamate.

In carrying out the process of the invention the lphenylcyclohexylamine compound can be introduced into the mammal either as the free base or as a non-toxic acid addition salt via the oral, rectal, nasal or parenteral route. By varying the amount of 1-phenylcyclohexylarnine compound employed different degrees of depressant-like effect upon the central nervous system can be produced which manifest themselves in effects ranging from euphoria to depression, a cataleptoid condition and anesthesia. Similarly different degrees of depressant-like effect upon the central nervous system can be produced by maintaining the amount of the l-phenylcyclohexylamine compound constant and varying the mode of administration. In the latter case, the depressant-like effect obtained by intramuscular injection is greater than that obtained by oral administration while intravenous injection produces a greater degree of depressant-like effect than that ohtaincd by either of these two methods. The varying degrees of depressant-like effect which can be produced by R the use of the process and compositions of the invention makes it possible to employ the invention for a number of different purposes. For example, it can .be used to produce euphoria, analgesia, sedation .and anesthesia. The process and compositions of the invention can also be used as an adjunct to surgical anesthesia. In this latto? respect they are especially useful as an adjunct for barbiturate anesthesia because they permit the use of mpch smaller quantities of the anesthetic agent thus eliminating or minimizing the undesirable side efiects so often 3,097,135 Patented July 9, 1963 encountered when the anesthetic agent is used alone in the customary manner. For example, in canine surgery an intravenous dose of 20 mg./ kg. of 5 -allyl-5-(1-methylbutyl)-2-thiobarbituric acid is required to produce a surgical anesthesia which will last for at least thirty minutes while a 10 mg./kg. intravenous dose ordinarily produces no evidence whatsoever of anesthesia. a surgical anesthesia lasting at least thirty minutes can be produced in canines by the intravenous administration of 10 m-g./ kg. of 5-allyl-5-(l-methylbutyl)-2-thiobarbituric acid if one first administers from 2 to 10 mg./kg., preferably 2 to 6 mg./kg., of one of the l-pllenylcyclohexylamine compounds of the invention intramuscularly and about fifteen minutes later administers the 10 mg./kg. of the 5-allyl-5-'(l-methylbutyl) -2-thiobarbituric acid. Thus the invention permits the use of from one-half to one-third the usual dos-age of 5-allyl-5(1 methylbutyl)-2- thiobarbituric acid and makes it possible to eliminate to a large extent the respiratory depression often associated with the normal use of this anesthetic agent.

The l-phenylcyclohexylamine compounds and their acid addition salts present in the compositions of the invention and used in the process of the invention possess an extremely high degree of activity and consequently only very small amounts are required to produce a marked depressant-like effect upon the central nervous system of mammals. For example, a cattaleptoid condition can be produced in dogs by the administration of 3 to 10 mg/ kg. orally or 1 to 10 mg./ kg. intramuscularly; in cats by the administration of 1 to 5 rug/kg. orally or about 1 mg./kg. intramuscularly; in monkeys by the administration of 5 to 20 mg./kg. intraperitoneally; 0.50 to 3 mg./kg. intravenously, 0.5 to 3 mg./kg. intramuscularly or 25 to 30 mg/kg. orally; and in adult humans by the administration of 0.1 mg. to 1.5 rug/kg. intramuscularly and 0.1 to 1.0 mg/kg. intravenously. In humans, a euphoric effect is produced by an oral dosage of 0.75 to 10 mg. The compositions and the process of the invention can be used to produce pro-operative sedation. In humans, the usual total dosage for this purp-ose'is about 5 to 50 mg. administered intramuscularly approximately one hour prior to the operation. The products and process can also be used to relieve the pain associated with birth. For this purpose, the dosage for humans is about 10 to 30 mg. administered intravenously or about 0.2 to 0.6 mg/kg. intramuscularly. The compositions and process of the invention are also useful in producing surgical anesthesia or as adjuncts to surgical anesthesia. In humans, the intravenous administration of 0.15 to 1 mg./k-g. produces a relatively complete blocking of all types of sensory input without significantly impariing consciousness or the normal circulatory and respiratory reflexes so that major operations can be performed anywhere on the body or within the abdominal or thoracic cavities. The preferred dosage is in the neighborhood of 0.25 mg./kg. intravenously. Surgical anesthesia in monkeys can be produced by the intravenous or intramuscular administration of about 7 to 15 mg./kg., in dogs by the intravenous administration of about 2 mg./kg. and in cats by the intramuscular administration of about 5 mg/kg. When used as an adjunct to barbiturate anesthesia, particularly, 5-allyl-5 (lmethylbutyl)-2-thiobarbituric acid anesthesia, the dosage in monkeys is about 0.25 to 1 mg./ kg. intravenously about ten to twenty minutes prior to the intravenous administration of 10 to 12.5 mg. of the thiobarbiturate and, in humans, about 0.1 to 0.2. mg./kg. intravenously prior to 250 to 350 mg. of the thiobarbiturate intravenously. Supplementary inhalation anesthesia canalso be employed with the process and compositions of the invention without adverse effects. In humans, the preferred supplementary inhalation anesthesia is 50 to 60% nitrous oxide-50 to 40% oxygen mixture. As a post operative analgetic,

However,

about to 50 mg. administered intramuscul arly is usually suflicient.

It will be appreciated that the degree of depressant-like effect produced in a given case is dependent not only on the species of mammal, dosage and method of administration but also on the idiosyncrasies of the individual treated and the particular l-phenylcyclohevylamine compound employed. For example, the (l-phenylcyclohexyl) ethylamine and 1-(l-phenylcyclohexyl)piperidine compounds produce a greater degree of depressant-like effect than the (1-phenylcyclohexyl)amine and (l-phenylcyclohexyl)dimethylamine compounds. in general, the variation in individual patient response is greater than the variation in response due to the use of the diiferent l-phenylcyclohexylamine compounds. 'In view of all of the fore- -going factors, the physician or veterinarian may find it advisable to adjust the dosage, in the light of individual patient response.

The compositions of the invention contain a l-phenylcyclohcxylamine compound having the formula given above or a non-toxic acid addition salt thereof together with a carrier. The carrier may be either a solid or liquid and the compositions can be in the form of tablets, liquid filled capsules, dry filled capsules, dragees, pills, aqueous solutions, non-aqueous solutions, jellies, suppositories, syrups, suspensions, sprays, powders and the like. The compositions can, and in many cases do, contain suitable preservatives, coloring and flavoring agents. Some examples of the carriers which can be use-d in the preparation of the products of the invention are gelatin capsules; sugars such as lactose and sucrose; cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose [and cellulose acetate ph-thalate; gelatin; talc; magnesium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; liquid petrol-atum, polyethylene glycol; glycerine; sorbitol; propylene glycol; ethanol; agar; water and isotonic saline.

In preparing the compositions of the invention for pharmaceutical purposes the conventional practices and precautions are used. The compositions intended for parenteral tad-ministration must be sterile and this can be accomplished either by using sterile ingredients and carrying out the production under aseptic conditions or by sterilizing the final composition by one of the usual procedures such as Seitz filtration. Ordinary care should be exercised that no incompatible condition exists between the active component and the diluent, preservative or flavoring agent or in the conditions employed in preparation of the compositions.

The compositions of the invention can, as mentioned above, be introduced into the mammal by the oral, rectal, nasal or parenteral route. This can be done by injecting the liquid preparations intravenously, intramuscularly, intraperitoneally or subcutaneously, by swallowing in the cases of the solid and liquid preparations, by local application to the mucous membranes in the case of jellies, sup positories and the like, by inhalation of sprays or mists of the liquid preparations and the like.

The preparation of the compositions of the invention is illustrated by the following examples.

(a) TABLETS Example 1 12.5 g. of 1-(1phenylcyclohexyl)piperidine hydrochloride is passed through a 60 mesh stainless steel screen and then thoroughly blended with 215 g. of milk sugar and 215 g. of sucrose containing 3% starch. The mixture is granulated with 40 g. of starch paste made from 1 part of starch and 7 parts of water. The granulation is dried and passed through a No. 20 screen. 17.5 g. of talc, 35 g. of corn starch and 1 g. of magnesium stearate are blended into the mixture and the mixture compressed into 4 inch concave tablets. Yield: 5000 tablets each containing 2.5 mg. of 1-(l-phenylcyclohexyl)piperidine hydrochloride.

Example 2 Fifty grams of l-phenylcyclohexylamine hydrochlon'de is passed through a 60 mesh, stainless-steel screen and then thoroughly blended with 180 g. of milk sugar and 215 g. of sucrose containing 3% starch. The mixture is granulated with 40 g. of starch paste made from one part of starch and seven parts of water. The granulation is dried and passed through a No. 20 screen. 17.5 g. of talc, 35 g. of corn starch and 1 g. of magnesium stearate are blended into the mixture and the mixture compressed into one-fourth inch concave tablets. Yield: about 5,000 tablets, each containing 10 mg. of l-phenylcyclohexylamine hydrochloride.

If desired, 50 g. of l-phenylcyclohexylamine acetate can be substituted for the hydrochloride salt used in the above procedure.

Example 3 12.5 g. of (l-phenylcyclohexyl)ethylamine hydrochloride is passed through a 60 mesh stainless-steel screen and then thoroughly blended with 215 g. of milk sugar and 215 g. of sucrose containing 3% starch. The mixture is granulated with 40 g. of starch paste made from one part of starch and 7 parts of Water. The granulation is dried and passed through a No. 20 screen. 17.5 g. of talc, 35 g. of corn starch and 1 g. of magnesium stearate are blended into the mixture and the mixture compressed into one-fourth inch concave tablets. Yield: 5,000 tablets each containing 2.5 mg. of (l-phenylcyclo hexyl) ethylamine hydrochloride.

If desired, 12.5 g. of (l-phenylcyc-lohexyl)ethylamine hydrobromide can be substituted for the hydrochloride salt used in the above procedure. Similarly 12.5 g. of (l-phenylcyclohexyl)-ethylamine sulfate can also be used in the above procedure.

Example 4 25 g. of (l-phenylcyclohexyl)diethylamine hydrochloride is passed through a 60 mesh stainless steel screen and then thoroughly blended with 215 g. of milk sugar and 215 g. of sucrose containing 3% starch. The mixture is granulated with 40 g. of starch paste made from 1 part of starch and 7 parts of Water. The granulation is dried and passed through a 20 mesh screen. 17.5 g. of talc, 35 g. of corn starch and 1 g. of magnesium stearate are blended into the mixture and the mixture compressed into one-fourth inch concave tablets. Yield about 5000 tablets each containing 5 mg. of (l-phenylcyclohexyl) diethylamine hydrochloride.

If desired, other salts of (l-phenylcyclohexyl)-diethyl amine can be substituted for the hydrochloride salt used in the above procedure. Similarly, one can employ 25 g. of (l-phenylcyclohexyl)dimethylamine hydrochloride in the above procedure to obtain tablets which contain 5 mg. of (l-phenylcyclohexyl)dimethylamine hydrochloride.

(b) DRY FILLED CAPSULES Example 5 g. of 1-(l-phenylcyclohexyl)piperidine hydrochloride is mixed with 500 g. of starch, 775 g. of lactose and g. of magnesium stearate and the resulting mixture filled into hard shell gelatin capsules holding mg. Yield 10,000 capsules each containing 10 mg. of 1-(1- phenylcyclohexyl)piperidine hydrochloride.

If desired, 1-(1-pheny1cyclohexyl)piperidine can be substituted for the hydrochloride salt.

Example 6 ilar salt can be substituted for the hydrochloride salt used in the foregoing procedure. If desired the free base of (l-ph-enylcyclohexyl)methylamine can also be used.

Example 7 100 g. of (1-phenylcyclohexyl)ethylamine hydrochloride is mixed with 1275 g. of starch and 125 g. of magnesium stearate and the resulting mixture filled into hard shell gelatin capsules holding 150 mg. each. Yield: 10,000 capsules each containing 10 mg. of (l-phenylcyclo- [hexyDethylamine hyrdochloride.

Example 8 100 g. of l-phenylcyclohexylamine p-toluenesulfonate is mixed with 1275 g. of lactose and 125 g. of magnesium stearate. The resulting mixture is filled into hard gelatin capsules holding 150 mg. each. Yield: 10,000 capsules, each containing 10 mg. of the p-toluenesulfonate salt of l-phenylcyclohexylamine.

Example 9 100 g. of l-phenylcyclohexylamine hydrochloride is mixed with 5370 g. of starch and 530 g. of magnesium stearate. The resulting mixture is filled into hard-shell gelatin capsules, each containing 150 mg. Yield: 40,000 capsules, each containing 2.5 mg. of l-phenylcyclohexylamine hydrochloride.

Example 10 100 g. of (l-phenylcyclohexyl)diethylamine hydro chloride is mixed With 1275 g. of starch and 125 g. of magnesium stearate. The resulting mixture is filled into hard shelled gelatin capsules each containing 150 mg. Yield: 10,000 capsules each containing 10 mg. of (l-phenylcyclohexyDdiethylamine hydrochloride.

() LIQUID FILLED CAPSULES Example 12 50 g. of 1-(1-phenylcyclohexyl)piperidine is dissolved in 4950 g. of sesame oil and the resulting solution used in the production of soft gelatin capsules each containing mg. of 1-(l-phenylcyclohexyl)piperidine; yield: 10,000 capsules.

Example 13 200 g. of l-phenylcyclohexylamine is dissolved in 4800 g. of cottonseed oil and the resulting solution used in the production of soft gelatin capsules each containing 20 mg. of l-phenylcyclohexylamine; yield: 10,000 capsules.

Example 14 50 g. of (l-phenylcyclohexyl)isopropylamine is dissolved in 495 0 g. of cottonseed oil and the resulting solution used in the production of soft gelatin capsules each containing 5 mg. of (l-phenylcyclohexyl)isopropylamine;

yieldz 10,000 capsules.

Example 15 100. g; of (1-phenylcyc1ohexyl)methylethylamine is (dissolved in 4900 g. of cottonseed oil and the resulting slolution used in the production of soft gelatin capsules ench containing-10 mg. of (l-phenylcyclohexyl)methylethylamine. Yield: about 10,000 capsules.

6 (d) I NJECTABLE SOLUTIONS (AQUEOUS) Example 16 20 g. of 1-(1-phenylcyclohexyl)piperidine hydrochloride is dissolved in 8 liters of pyrogen free water for injection buffered to a final pH of 5. 5 with a citric acid butter and the resulting solution filled into ampoules containing 1.2 ml. under sterile conditions so that 1 ml. containing 2.5 mg. of 1-(l-phenylcyclohexyl)piperidine hydr-ochloride can be removed.

Example 17 g. of l-phenylcyclohexylarnine hydrochloride is dissolved in 4 liters of pyrogen-free water for injection. A citrate butler designed to bring the pH to 5.5 is added, and the solution is diluted to a volume of 8 liters. The resulting solution is filled into ampoules containing 1.2 ml. under sterile conditions so that 1 ml. containing 10 mg. of l-phenylcyclohexylamine hydrochloride can be removed.

Example 18 20 g. of (l-phenylcyclohexyl)ethylamine hydrochloride is dissolved in 8 l. of py-rogenfree water for injection and buffered to a final pH of 5.5 with a citric acid butter. The resulting solution is filled into ampoules containing 1.2 ml. under sterile conditions so that 1 ml. containing 2.5 mg. of (l-phenylcyclohexyl)ethylamine hydrochloride can be removed.

Example 19 40 g. of (l-phenylcyclohexyl)diethylamine hydrochloride is dissolved in 4 1. of pyrogen-firee Water for injection containing a citric acid buffer designed to bring the final pH of the solution to 5.5. The solution is filtered and diluted to a volume of 8 1. With pyrogen free water for injection and then filled into ampoules containing 1.2 ml. The filling is carried out under sterile conditions and the ampoules filled so that 1 ml. containing 5 mg. of (1- phenylcycl ohexyl)diethylamine hydrochloride can be removed.

(e) INJECTABLE SOLUTIONS (NON-AQUEOUS) Example 20 25 g. of 1-( 1-phenylcyc1ohexyl)piperidine is dissolved in 10 liters of peanut oil containing 10 g. of benzyl alcohol. 1.2 portions of the resulting solution are filled into ampoules under sterile conditions so that 1 ml. con taining 2.5 mg. of 1-(l-phenylcycl ohexyl)piperidine can be removed.

Example 21 g. of l-phenylcyclohexylamine is dissolved in ten liters of peanut oil containing 10 g. of benzyl alcohol. 1.2 ml. portions of the resulting solution are filled into ampoules under sterile conditions so that one ml. containing 10 'mg. of l-phenylcyclohexylamine can be removed.

Example 22 50 g. of (1 phenylcyclohexyl)methylethylamine is dissolved in 10 1. of peanut oil containing 10 g. of benzyl alcohol. 1.2 ml. portions of the resulting solution are filled into ampoules under sterile conditions so that 1 ml. portions oontaining 5 mg. of (1-phenylcyclohexyl)methylethylamine can be removed.

(1) SUPPOSITORIES Example 23 10 g. of 1-(l-phenylcyclohexyl)piperidine hydrochloride is blended with 1200 g. of oil of theobroma and the resulting mixture formulated into suppositories each containing 25 mg. of 1-(1-phenylcyclohexyl)piperidine hydrochloride. Yield: about 400 suppositories.

,sulting solution.

Example 24 10 g. of l-phenylcyclohexylamine hydrochloride is blended with 1200 g. of oil of theobroma and the resulting mixture formulated in suppositories each containing 25 mg. of l-phenylcyclohexylamine hydrochloride. Yield: about 400 suppositories.

Example 25 10 g. of (:l-phenylcyclohexyl)ethylamine hydrochloride is blended with 1200 g. of oil of theobroma and the resulting mixture formulated into suppositories each containing 25 mg. of (l-phenylcyclohexyl)ethylamine hydrochloride. Yield: about 400 suppositories.

Example 26 10 g. of (l-phenylcyclohexyl)dimethylamine hydrochloride is blended with 1200 g. of oil of theobroma and the resulting mixture formulated into suppositories each containing 25 mg. of (l-phenylcyclohexyl)dimethylamine hydrochloride. Yield: about 400 suppositories.

(g) SYRUPS Example 27 containing 120 ml. Each ml. of this syrup contains 2.5

mg. of 1-(1-phenylcyclohexyl)piperidine hydrochloride.

Example 28 6 g. of l-plienylcyclohexylamine and 1.5 ml. of oil 0 orange are dissolved in 400 ml. of glycerine. 300 ml. of water is added to the solution and then 100 g. of sucrose and 100 g. of sorbitol dissolved in the resulting mixture. The solution is filtered to clarify it and the filtrate diluted to a vourne of one liter with Water. The resulting solution is filled into bottles containing 15 ml. each. Each ml. of this solution contains 6 mg. of l-phenylcyclohexylamine.

Example 29 1.25 g. of l-phenylcyclohexylamine hydrochloride is dissolved in 400 ml. of water and 200 g. of sucrose dissolved in the resulting solution. 100 g. of sorbitol is dissolved in the solution and 1.5 ml. of oil of orange and 1 g. of sodium henzoate added. The solution is filtered, the filtrate diluted to one liter with water and the diluted solution filled into bottles containing 20 ml. Each ml. of the solution so obtained contains 1.25 mg. of l-phenylcyclohexylamine hydrochloride.

Example 30 contains 1.5 mg. of '(l-phenylcyclohexyl)ethylamine.

Example 31 1.5 g. of (l-phenylcyolohexyl)ethylamine hydrochloride is dissolved in 400 ml. of water and 200 g. of sucrose dissolved in the resulting solution. 100 g. of sorbitol is dissolved in the solution and 1.5 ml. of oil oat orange and 1 g. of sodium benzoate added. The solution is filtered,

the filtrate diluted to 1 liter with Water and the diluted solution filled into bottles containing 20 ml. Each ml. of the solution contains 1.5 mg. of (l-phenylcyclohexyD- ethylamine hydrochloride.

Example 32 2.5 g. of (l-phenylcyclohexyl)ethylamine hydrochloride is dissolved in 4 liters of water. 4000 g. of sucrose and 2000 g. of sorbitol are dissolved in the solution. 10 g. of sodium benzoate, 1 ml. of oil of peppermint and 1 ml. of oil of lime are added to the solution and resulting solution diluted to 10 liters with water. The liquid is strained and then filled into bottles containing 120 ml. Each 5 ml. of this syrup contains 1.25 mg. of (l-phenylcyclohexyl) ethylann'ne hydrochloride.

Example 33 3 g. of (l-phenylcyclohexyl)methylethylamine and 1.5 ml. of oil of orange are dissolved in 400 ml. of glycer'ine. 300 ml. of water are added to the solution and then g. of sucrose and 100 g. of sorbitol dissolved in the solution. The solution is filtered to clarify it and the filtrate diluted to 1 liter with Water. The resulting solution is filled into bottles containing 15 ml. each. Each ml. of the solution contains 3 mg. of (1-phenylcyclohexyl)methylethylamine.

Example 34 3 g. of =(l-phenylcyclohexyl)diethylamine hydrochloride is dissolved in 400 ml. of water and 200 g. of sucrose dissolved in the resulting solution. 100 g. of sorbitol is dissolved in the solution and 1.5 ml. of oil of orange and 1 g. of sodium benzoate added. The solution is filtered, the filtrate diluted to 1 liter with water and the diluted solution filled into bottles containing 20 ml. each. Each ml. ofthe solution contains 3 mg. of (l-phenylcyclohexyl) diethylamine hydrochloride.

Example 35 5 g. of (1-phenylcyclohexyl)methylethylamine hydrochloride is dissolved in 4 l. of water. 4000 g. of sucrose and 2000 g. of sorbitol is dissolved in the solution. 10 g. of sodium benzoate, 1 ml. of oil of peppermint and '1 ml. of oil of lime are added to the solution. The resulting solution is diluted to 10 ml. with Water and strained. T he syrupy liquid is filled into bottles of ml. each. Each 5 ml. of the syrup contains 2.5 mg. of (l-phenylcyclohexyl)methylethylamine hydrochloride.

The l-phenylcyclohexylamine compounds and their non-toxic acid addition salts used in the practice of the invention can be prepared in a number of ways. For example, the l-phenylcyclohexyl)monoaikyl amines can be prepared by reacting a Schifi base derived from cyclohexanone with a phenyl alkali metal compound and decomposing the resul'tlng product with water. The (1- phenylcyclohexyl)dialkylamines and 1'(l-p henylcyclo hexyl)heterocyclic amines can be prepared by reacting a quaternary ammonium salt of formula,

Example A A mixture consisting of 100 g. of anhydrous ethylarnine and 220 g. of cyclohexanone is allowed to stand for 16,

hours.

decant'ation. Distillation of the oil layer in vacuo yields the desired N-cyclohexylidene ethylamine; B.P. 68-75 at 22 mm.

A solution of phenyllithium prepared from 11.2 g. o

The reaction mixture is shaken thoroughly with; solid potassium hydroxide and the oil layer removed by lithium and 76 ml. of bromobenzene in 500 m1. of ether is added dropwise at C. to a solution of 51 g. of N- cyclohexyllidene ethylamine in 500 ml. of ether. After the addition has been completed, the reaction mixture is stirred for one hour and then decomposed by the addition of water. The ether layer is removed, washed with water and dried. The ether is evaporated and the residue distilled in vacuo to obtain the desired l-phenylcyclohexyly ethylamine; B.P. 104-108 C. at 2.5 mm.

The hydrochloride salt of (1-phenylcyclohexyl)ethylamine is prepared by dissolving the free base inan excess of isopropanolic hydrogen chloride, precipitating the salt with ether and recrystallizing the product so obtained from etheraisopropanol mixture; M.P. 236-237" C.

Example B A mixture consisting Off 170 g. of piperidine, 220 g. of cyclohexanone and 750 ml. of benzene is subjected to azeotropic distillation until the evolution of water ceases. The solution is subjected to vacuum distillation to obtain the desired l-(Lcyclohexenyl)piperidine; B.P. 105 C. at 8 mm.

190 g. of p-toluenesulfonic acid monohydrate is suspended in 250 ml. of toluene and the mixture heated under a water trap until all the water has been removed. 165 g. of 1-(1-cyclohexeneyl)piperidine in 500 ml. of ether is added to the toluene solution of p-toluenesulfonic acid at about 0 to C. A solution of approximately one mole of phenylmagnesium bromide (prepared from 157 g. of bromobenzene and 24 g. of magnesium) in 750 ml. of other is added to the slurry of the p-toluenesulfonate salt of 1-(1-cyclohexeneyl)piperidine with stirring at about 5 C. The reaction mixture is stirred for 30 minutes after the addition has been completed and then decomposed by the addition of an excess of saturated ammonium chloride and concentrated ammonium hydroxide. The ether layer is removed, dried over potassium carbonate and the ether distilled. Distillation of the residue in vacuo yields the desired 1-( l-phenylcyclohexyl)piperidine; B.P. 135-137 C. at 1 mm; M.P. 46-465 C.

The hydrochloride salt is prepared by dissolving the free base in ether, adding an excess of hydrogen chloride to the solution, collecting the crude product and purifying by recrystallization from methanol-ether mixture; M.P. 243244 C. The hydrobromide salt can be prepared in a similar manner by substituting hydrogen bromide for the hydrogen chloride used in the preparation of the hydro chloride salt.

The sulfate salt of 1-(l-phenylcyclohexyl)piperidine can be prepared by adding the free base to an alcohol solution containing one equivalent of sulfuric acid. The salt is precipitated by the addition of ether and purified by recrystallization from methanol-ether mixture.

Example C 142 g. of iodomethane in 150 ml. of ether is added to a solution of 125 g. of cyclohexylidene-ethylamine (prepared by the action of ethylamine on cyclohexanone) in 15 0 ml. of ether and the resulting solution warmed to 30 C. for two hours with occasional stirring. The reaction mixture which contains the desired quaternary ammonium compound is then heated briefly on a steam bath and then diluted with 750 ml. of ether. A solution of one mole of phenyl lithium in 750 ml. of ether is added to the mixture containing the quaternary ammonium compound while stirring and cooling and the resulting mixture stirred and refluxed for 30 minutes after the addition has been completed. The reaction mixture is decomposed by the 10 cautious addition of 500 ml. of water and the ether layer is removed and dried. The ether is distilled and the residue is subjected to distillation in vacuo to obtain the desired (l-phenylcyclohexyl) ethylmethylamine; B.P. 8 C. at 0.12 mm.

The hydrochloride salt of (l-phenylcyclohexyl)ethylmethylamine can be prepared by dissolving the free base in ether and treating the resulting solution with an excess of isopropanolic hydrogen chloride. The salt is collected and purified by recrystallization from isopropanol-ether; M.P. 194-5 C.

The hydrobromide salt of (l-phenylcyclohexyl)ethylmethylamine can be prepared in the same manner by using dry hydrogen bromide instead of dry hydrogen chloride.

The p-toluenesulfonate salt of (1-phenylcyclohexyl)- ethylmethylamine can be prepared by adding an ethanol solution of the free base to an ethanol solution containing an excess of p-toluenesulfonic acid. The salt is precipitated by the addition of ether and purified by recrystallization from methanol-ether mixture.

This application is a continuation in part of Ser. Nos. 684,848, 684,849, 684,855 and 684,864. The four applications were filed on September 19, 1957. This application is also a continuation in part of Ser. Nos. 710,388, 710,389, 710,390 and 710,391. These four applications were filed on January 22, 1958. All of the foregoing applications are now abandoned.

We claim:

1. Process for producing a depressant-like eifect upon the central nervous system of a mammal which comprises introducing into a mammal a member of the class consisting of a l-phenylcyclohexylamine compound and nontoxic acid addition salts thereof; said l-phenylcyclohexylamine compound having the formula,

where R and R are members of the class consisting of hydrogen and lower alkyl radicals, the sum of carbon atoms in said R and R being less than 5, and further members wherein R and R are combined and together represent a polymethylene radical containing more than 3 and fewer than 7 carbon atoms.

2. Process for producing a depressant-like efiect upon the central nervous system of a mammal which comprises introducing a non-toxic acid addition salt of 1-(1-phenylcyclohexyl)piperidine into a mammal.

3. Process for producing a depressant-like effect upon the central nervous system of a mammal which comprises injecting an aqueous solution of a non-toxic acid addition salt of 1-(-phenylcyclohexyl)piperidine into a mammal.

4. Process for producing a depressant-like effect upon the central nervous system of a mammal which comprises introducing a non-toxic acid addition salt of l-phenylcyclohexyl)ethyla'mine into a mammal.

5. Process for producing a depressant-like effect upon the central nervous system of a mammal which comprises injecting an aqueous solution of a non-toxic acid addition salt of (l-phenylcyclohexyl)ethylamine into a mammal.

References Cited in the file of this patent Kursanov: Chem. Abst, vol. 1, page 2093, 1907. 

1. A PROCESS FOR PRODUCING A DEPRESSANT-LIKE EFFECT UPON THE CENTRAL NERVOUS SYSTEM OF A MAMMAL WHICH COMPRISES INTRODUCING INTO A MAMMAL A MEMBER OF THE CLASS CONSISTING OF A 1-PHENYLCYCLOHEXYLAMINE COMPOUND AND NONTOXIC ACID ADDITION SALTS THEREOF; SAID 1-PHENYLCYCLOHEXYLAMINE COMPOUND HAVING THE FORMULA, 1-(R1-N(-R2)-),1-(H5C6-)-CYCLOHEXANE WHERE R1 AND R2 ARE MEMBERS OF THE CLASS CONSISTING OF HYDROGEN AND LOWER ALKYL RADICALS, THE SUM OF CARBON ATOMS IN SAID R1 AND R3 BEING LESS THAN 5, AND FURTHER MEMBERS WHEREIN R1 AND R2 ARE COMBINED AND TOGETHER REPRESENT A POLYMETHYLENE RADICAL CONTAINING MORE THAN 3 AND FEWER THAN 7 CARBON ATOMS. 